The present invention relates to compositions and devices for conferring to wound dressings anti-infective activity.
Wound dressings absorb and draw off excess blood, serum and pus in maintaining a clean site conducive to healing. They also aid healing by controlling and restricting water loss. Too much retention of water over the wound site can result in maceration of the skin and impaired healing. Too much loss can lead to hypotherinia and severe electrolyte imbalances, especially in the case of burn patients. Materials used in the manufacture of wound dressings include woven fibers, porous foam pads, and cast hydrogels made up of cellulose and its derivatives (cellulosics), polyesters, nylon, polyacrylamides, polyurethanes, and collagen. The exudation of serum and blood from wounds to the external environment, and the difficulty in maintaining a sterile site, can lead to serious infection because this rich medium when trapped in wound dressings which also maintain a moist environment provides an opportune site for bacterial growth. The definition of a wound dressing as used in this context includes dressings designed to cover compromised skin including tears to the skin caused by blunt trauma, burns, punctures, ulcerations of the skin in which an exudate occurs, etc.
Other conditions at the wound site also occur which promote bacterial growth. First, the bicarbonate buffer system of blood depends upon the dissolution of gaseous carbon dioxide into blood, and its hydration to carbonic acid (catalyzed by carbonic anhydrase present in great abundance in red blood cells) in balancing the blood pH. The equilibrium between the gaseous form of carbon dioxide and bicarbonate lies several thousand fold in favor of the gaseous form of carbon dioxide. In an open wound carbon dioxide is rapidly lost to the atmosphere. This loss of carbon dioxide drives the wound site toward a more alkaline environment, a condition favorable to bacterial growth. Second, the oxygen tension drops precipitously as a consequence of bacterial growth, tissue metabolism, the loss of vascularization and adequate perfusion, and the poor solubility of oxygen across the aqueous interface of the wound site. This is further aggravated by the diffusion barrier of wound dressing materials which restrict free exchange of oxygen. Since the body""s phagocytic defense system requires oxygen to generate an anti-infective defense (Klebanoff, S. J. and Clark, R. A. (1978) in The Neutrophil: Function and Clinical Disorders, North-Holland Publishing Company, Amsterdam), the decreased availability of oxygen impedes phagocytic killing reactions which otherwise help ward off infections. Although studies show there is an overall drop in the pH of fluid within wound sites by about a half pH unit below the normal blood pH within hours of application of a wound dressing, about a two-fold increase in dissolved carbon dioxide above normal blood levels, and a precipitous drop in oxygen tensions by 10 to 20 fold below that found in normal blood (Ninikoski, J., Heughan, C. and Hunt, T. K. (1971) Surgery, Gynecology and Obstetrics 133: 1003-1007; Varghese, M. C. et al. (1986) Arch Dermatol 122: 52-57; Katz, S., McGinley, K. and Leyden, J. J. (1986) Arch Dermatol 122: 58-62; Sirvio, L. M. and Grussing, D. M. (1989) J Invest Dermatol 93: 528-531), this is the result of two opposing reactions: (i) an initial loss of dissolved carbon dioxide from the wound site concomitant with alkalinization of the wound which promotes conditions conducive to bacterial growth and infection; and (ii) a subsequent sharp fall in oxygen tension concomitant with bacterial propagation and tissue respiration coupled with the poor diffusibility of oxygen across the air-water interface of the wound site. Lactic acidosis also ensues. In deep wounds these conditions can create serious, pus loaded abscesses infected with anaerobic bacteria requiring surgery and drainage. In some instances, without proper infection control, life-threatening septicemia may ensue.
Iodine is a potent anti-infective agent with much promise as an affective agent in preventing infections associated with wound care. It has been used for over 150 years in various formulations as a sterilizing agent. Examples include tincture of iodine (an alcoholic solution of free iodine and inorganic iodide), Lugol""s solution (a strong mixture of aqueous inorganic iodide and iodine), and in varying complexed forms of elemental iodine using water-soluble iodophors such as polyvinylpyrrolidone (Povidone-iodine) or iodine-bound cadexomers (biodegradable carbohydrate polymer complexes mixed together with elemental iodine formulated in polyethylene glycol). Iodine exists in several oxidation states including its fully reduced iodide (Ixe2x80x94) state in addition to its oxidized diatomic free elemental state (I2), and in several higher oxidation states in combination with oxygen (e.g., hypoiodate (IOxe2x80x94), iodate (IO3xe2x80x94) and periodate (IO4xe2x80x94)). In aqueous solutions iodide forms an equilibrium complex with elemental iodine, yielding soluble tri-iodide (I3xe2x80x94), a bound form of iodine devoid of microbicidal activity. Several studies have shown that it is the free form of iodine which exhibits microbicidal activity.
Iodine is difficult to handle in the free form, however, because it is chemically reactive with a number of substances in, and outside, of the body. It is also volatile and readily escapes into the atmosphere. Methods of trapping it in a semistable form involve complexation as an iodophor (e.g. complexed forms of elemental iodine in solution using specific organic binding agents). Among the better known iodofors is Povidone-Iodine, also known as Betadine(copyright), a water soluble polyvinylpyrrolidone organic polymer mixed with inorganic iodide and elemental iodine. In this formulation most of the elemental iodine present binds to the hydrophobic polyvinylpyrrolidone backbone as well as to the cationic pyrrole nitrogen in the form of a tri-iodide complex, none of which forms exhibit any microbicidal activity.
Free elemental iodine is only a small fraction of the total iodine in Povidone-Iodine. 10% Povidone-Iodine, for example, is formulated at xcx9c1% total xe2x80x9cavailablexe2x80x9d iodine (e.g., 10,000 ppm). Its free elemental iodine concentration varies from xcx9c0.8 to 1.2 ppm (Ellenhorn""s Medical Toxicology: Diagnosis and Treatment of Human Poisoning, 2nd edition). LeVeen et al. (Surgery, Gynecology and Obstetrics 176:183-190, 1993) have pointed out several deficiencies in Povidone-Iodine formulations for the treatment of wounds including low free elemental iodine levels of marginal efficiency as an anti-infective. They noted that the low level of free iodine is ineffective except against extremely sensitive bacteria. Polyvinylpyrrolidone also contaminates the wound site and has been noted to cause granulomas in wounds. LeVeen et al., and later Shikani and Domb (J. Amer. College of Surgeons 183:195-200, 1996), sought to get around these problems by dissolving elemental iodine into polyurethane, a water insoluble polymer with iodine binding properties. Various iodine loaded polyurethane patches have evolved through this approach (U.S. Pat. No. 5,762,638). Iodine impregnated polyurethane dressings are not easily produced with uniform and predictable levels of free iodine, however, as it is difficult to control retention of iodine in a polyurethane polymer base. Iodine trapped in this manner not only diffuses free of the polymer base creating problems regarding shelf-life storage and handling of the wound dressing material, but it is also reactive and can be consumed before it comes into contact with wound fluid.
Alternative approaches for sequestering free iodine have included its complexation in biodegradable carbohydrate polymeric hydrogels (U.S. Pat. No. 4,783,448; U.S. Pat. No. 4,010,259). In the latter hydrogel formulations, the iodine content is stated to preferably range from a low of about 0.4% to about 2% (wet weight of gel). These formulations are unstable for the same reasons that Povidone-iodine is unstable.
There are other significant drawbacks inherent in the formulation of these iodofor wound dressings. The high iodine content poses a serious toxicological limitation in their application, especially regarding their use over large surface areas of the body. This is because iodine, formulated in these types of dressings, is readily absorbed by the body and concentrated in the thyroid gland. Excess iodine taken into the body leads to hypothyroidism through a shutdown and atrophy of the thyroid gland. Whereas the essential daily intake needs of the body for iodine is in the range of 150 to 200 micrograms per day, and the upper safe threshold is believed to be no greater than about 1000 micrograms per day (Ensininger, A. H. et al. (1993) in Foods and Nutrition Encylopedia, 2nd edition, CRC Press), it takes very little exposure to iodofor formulations to exceed this level of intake. For example, a one gram formulation containing 0.4% by weight iodine complexed in a carbohydrate polymer (U.S. Pat. Nos. 4,010,259 and 4,783,448) is the equivalent of 4,000 micrograms (e.g., 0.004 grams) total iodine, or an amount four times the recommended upper daily safe intake threshold. For Povidone-iodine impregnated bandages, the high total iodine content (e.g., 10%) likewise restricts the use of these formulations to very small areas of the body, and for limited duration.
Montgomery et al. (U.S. Pat. No. 4,576,817) claim the use of glucose oxidase in combination with lactoperoxidase and iodide as a potent anti-infective wound dressing through formation of hypoiodite. They provide neither data nor information as to how hypoiodite, the end-product formed, could be made in a wound site lacking significant oxygen tensions required for the formation of hydrogen peroxide. This is problematic since oxygen is an obligatory substrate in the scheme proposed in their patent. Furthermore, while acknowledging that catalase present in a wound site competes for hydrogen peroxide formed by the glucose oxidase reaction, they propose (but do not demonstrate) that levels of ascorbic acid added to their formulation in the range of from about 1 to 100 nanomoles per gram of material should be sufficient to block degradation of hydrogen peroxide required by lactoperoxidase in catalyzing formation of hypoiodite. They also propose adding iron. salts such as ferrous sulfate into the absorbent material of their wound dressings to potentiate ascorbate mediated inhibition of catalase. It is well-known, however, that the combination of iron salts and ascorbic acid in the presence of hydrogen peroxide generates hydroxyl radicals (Fenton chemistry), and that hydroxyl radicals attack multiple biological sites indiscriminately. Hence the scheme outlined by Montgomery et al. in U.S. Pat. No. 4,576,817 would not ensure selective inhibition of catalase, but rather inactivation of any enzyme (including glucose oxidase and lactoperoxidase) coming into contact with the short-lived, but powerful hydroxyl radical oxidizing agent. Other limitations include: (i) competition by hemoglobin (a pseudoperoxidase) in consuming hydrogen peroxide; (ii) the instability of ferrous salts in aqueous solution and conversion to insoluble ferric hydroxide complexes which precludes any anticipated lasting effect of this formulation as far as a role of ferrous salts is concerned; and (iii) the rapid and aggravating depletion of dissolved oxygen in a wound site environment caused by dissolution of ferrous salt into wound fluid as a result of the well-known spontaneous reaction of the ferrous salt with dissolved oxygen in solution.
EP 0 307 376 A1 similarly proposes to use oxidoreductases in combination with a peroxidase and inorganic iodide, or an alternate hydrogen peroxide source such as magnesium or percarbamide, to be formulated in the pH range of from about 3.5 to 6.0, as a wound dressing treatment. Aside from the limitations already noted in generating hydrogen peroxide in a semi-anaerobic environment, there is no explanation in EP 0307376A1 as to how the formulation is presented in a wound dressing. The compositions proposed are described only as xe2x80x9c. . . a pure dry pulverulent mixturexe2x80x9d or xe2x80x9cin the form of tablets and granules as well as double layer tablets which are dissolved . . . xe2x80x9d In using magnesium or percarbamide as the hydrogen source, the patent does not address how hydrogen peroxide released would be spared degradation by catalase and other heme proteins common to the wound site.
The invention is directed to a wound dressing having anti-infective activity. In one embodiment the wound dressing generally comprises a sheet comprising a crosslinked polymeric matrix, and an oxidant generating formulation contained within or on the polymeric matrix, the polymeric matrix being impermeable to reactants such as bacteria, catalase, and proteins, present in the wound site. The polymeric matrix is impermeable to the reactants from the from the body fluid which would be capable of reacting with hydrogen peroxide and oxygen in the sheet. In one embodiment, the crosslinked polymeric matrix comprises polyacrylamide. In aspect of the invention, the oxidant generating formulation is stable at least until contacted by a substrate, such as glucose, which is permeable into the polymeric matrix from the patient""s body fluid at the wound site. In a presently preferred embodiment, the anti-infective oxidant generated by the oxidant generating formulation is elemental iodine.
In one embodiment, the wound dressing of the invention is a single, or xe2x80x9cmonoxe2x80x9d layer. In the monolayer embodiment, the dressing has the oxidant generating formulation, or at least a part thereof, in a single layer. However, the single layer may comprise a plurality of stacked layers, provided the plurality of layers all have the same composition. In an alternative embodiment, the wound dressing is multilayered having a first part of the oxidant generating formulation in a first layer, and a second part of the oxidant generating formulation in one or more additional layers.
In one embodiment of the invention, the multilayered wound dressing generally comprises a first sheet having an iodide, an oxidant or oxidant generator impregnated therein and a second sheet having a proton donor. In one embodiment, the first sheet comprises a hydrophobic polymer having a microcannular structure releasably containing the iodide and oxidant or oxidant generator. In another embodiment, at least one of the first and second sheet comprises a lyophilized hydrogel.
The present invention provides for stable and improved formulations of precursors required in generating anti-infective iodine specifically within a wound site where the oxygen tension may be very low. Furthermore, the design of the invention precludes interference by catalase (and other heme proteins) in competing for hydrogen peroxide where hydrogen peroxide is used as a component of the iodine generating formulation, ensuring more efficient and sustained production of free iodine as a potent anti-infective agent. The invention takes advantage of the physical design of the wound dressing, and the permeation of body fluid into the dressing, which together serve to initiate formation of nascent iodine concomitant with placement of the dressing into, or over, a wound site. The invention circumvents the problem of trapping elemental iodine in the form of tri-iodide, which lacks microbicidal activity, by the chemical method of generating iodine de novo, and in the presence of excess oxidant. Newly formed iodine is thus able to egress and disperse throughout the wound site before there is an opportunity for it to become fully bound as tri-iodide, conferring to the wound site anti-infective activity. Two embodiments of the wound dressing invention are described comprising a mono- and bilayer configuration which, when placed in a wound site, confer to the site anti-infective properties.